A number of respiratory infections are known to be caused by microbes such as S. pneumoniae, S. aureus, C. pneumoniae, H. influenzae, M. catarrhalis, M. pneumoniae, and L. pneumophila. Many of these microbes are able to develop rapid resistance to commonly used antibiotic agents such as penicillin, oxacillin, flucloxacillin, and methicillin. In particular S. aureus exhibits a robust ability to acquire resistance to antibiotic agents (whether by acquisition of resistance genes or developing novel resistance mechanisms). One S. aureus strain, for example, has developed a broad-based resistance to common “front line” antibiotics (all β-lactams) as well as to antibiotics of “last resort” such as Vancomycin. This strain has been termed “MRSA” (methicillin-resistant Staphylococcus aureus) and presents a particular public health concern because it is not only involved with mild skin and soft tissue infections (e.g., folliculitis), but also can cause more serious respiratory infections (e.g., pneumonia) as well as sepsis, osteomyelitis, septic arthritis, endocarditis, and toxic shock syndrome. S. aureus is also a leading cause of primary infections originating in hospitals.
Several broad-spectrum antibiotics are currently used to treat of S. aureus infections. These antibiotics commonly target any number of biochemical pathways including cell-wall biosynthesis (e.g., β-lactams and vancomycin), bacterial protein synthesis (e.g., erythromycins, tetracyclins, amino-glycosides and oxazolidinones) and bacterial DNA replication and repair (e.g., fluoroquinolones). As microbial strains have developed resistance to a number of commonly used antibiotics, the efficacy of these known active agents has decreased severely.
Drug resistant S. aureus strains include modifications in surface proteins that promote colonization of host tissues, biochemical variations that enhance survival in phagocytes and evasion of the host immune system, enhanced release of toxins that lyse eukaryotic cell membranes and active efflux of antibiotics coupled with mutation events in target molecules that abrogate the action of drugs, among others.
Accordingly the continued development and discovery of compounds that can inhibit biological activity of infective microbial organisms, such as methicillin-resistant S. aureus, will aid providing more successful outcomes for subjects with microbial infections and conditions related to such infections. Further, continued development of methods for accurately identifying infective microbial organisms will more effectively address this public health issue.